Important Information on Estraderm Continued from Previous Page Estraderm@ estradiol transdermal system Continuous delivery for twice-weekly application BRIEF SUMMARY (FOR FUU PRESCRIBING INFORMATION, SEE PACKAGE INSERT) ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA. Three Independent case control studies have reported an Increased nsk of endometnal cancer In postmenopausal women exposed to exogenous estro- gens for more than 1 year This nsk was Independent of the other known nsk factors for endometnal cancer These studies are further supported by the finding that incidence rates of endometnal cancer have Increased sharply Since 1969 10 eight different areas of the United States with population-based cancer-reporting systems, an Increase which may be related to the rapld expanding use of estrogens dunng the last decade The three case control studies reported that the nsk of endometnal cancer In estrogen users was about 4 5-13 9 times greater than 10 nonusers The nsk appears to depend both on duration oftreatment and on estrogen dose Invlew of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible When prolonged treatment IS medically mdlcated, the patient should be reassessed on at least a semiannual basIs to determine the need for continued therapy Although the evidence must be considered preliminary, one study suggests that cyclic administratIon of low doses of estrogen may carry less nsk than contmuous administration, It therefore appears prudent to utilize such a regimen Close clinical surveillance of all women taking estrogens IS Important In all cases of undiagnosed persistent or recurnng abnormal vaginal bleedmg, ade- quate diagnostic measures should be undertaken to rule out malignancy There IS no eVidence at present that 'natural" estrogens are more or less hazardous than 'synthetlc" estrogens at equlestrogemc doses ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. The use of female sex hormones, both estrogens and progestogens dunng early pregnancy may senous damage the offspnng It has been shown that women who had been exposed In utero to diethylstilbestrol, a nonsteroidal estrogen, have an Increased nsk of developing In later life a form of vaginal or cervical cancer that IS ordman extreme rare This nsk has been estimated as not greater than 4 per 1000 exposures Furthermore, a high percentage of such exposed women (30-90%) have been found to have vaginal adenosls, epithe- lial changes ofthe vagina and cerviX Although these changes are histologically benign, it IS not known whether they are precursors of malignancy Mhough similar data on the use of other estrogens are not aVailable rt cannot be presumed they would not mduce similar changes Several reports suggest an assoCIation between Intrautenne exposure to female sex hormones and congenital anomalies, including congenital heart defects and limb-reduction defects One case control study estimated a 4 7- fold Increased nsk of limb-reduction defects 10 Infants who had been exposed In utero to sex hormones (oral contraceptives, hormone withdrawal tests for pregnancy, or attempted treatment for threatened abortion) Some of these exposures were very short and Involved only a few days of treatment The data suggest that the nsk of limb-reduction defects 10 exposed fetuses IS somewhat less than 1 per 1000 In the past, female sex hormones have been used dunng pregnancy 10 an attempt to treat threatened or habitual abortion. There IS considerable eVidence that estrogens are meffectlve for these indications and there IS no eVidence from well-controlled studies that progestogens are effective for these uses If Estraderm IS used dunng pregnancy, or IT the patient becomes pregnant while taking this drug she should be appnsed of the potential nsks to the fetus and of the advisability of continuation of the pregnancy INDICATIONS AND USAGE Estraderm IS mdlcated for the treatment of the following moderate-to-severe vaso- motor symptoms assoCIated with menopause, female hypogonadism. female castra- tion, pnmary ovanan failure; and atrophic conditions caused by defICIent endogenous estrogen production, such as atrophic vaginitis and kraurosIs vulvae; and prevention of osteoporosIs (loss of bone mass) Estrogen replacement therapy IS the most effectIVe smgle modality for the preven- tion of postmenopausal osteoporosIs In women Case-controlled studies have shown a reduction of approximately 600 10 the mCldence of hip and wnstfractures 10 women who began estrogen replacement therapy within a few years of menopause A recent, well-controlleó, double-blind, prospective tnal conducted at the Mayo Clinic has demonstrated that treatment WIth Estraderm prevents bone loss In postmenopausal women at a dosage of 0 05 mg per day Treatment With Estraderm 0 05 mg showed full maintenance of bone density with slight (0 8%), but not significant. Increase Placebo treatment resulted In a significant loss of more than 6% below baseline vertebral bone mass Patients usmg either Estraderm 0 1 mg or 0 05 mg had slgnITlcantly greater bone densities than those usmg placebo Other studies suggest that estrogen replacement therapy reduces the rate of vertebral fractures - Peak bone mass IS reached at age 30 to 35 and can best be maximIZed by adequate calCIum Intake and exerctse dunng the adolesænt and early adufi years Early meno- pause IS one of the best predictors forthe development of osteoporosIs White women are at higher nsk for osteoporosIs than white men black women are at higher nsk than black men, and thin women are at higher nsk than obese women Cigarette smoking may be an additional nsk factor Calcium defICIency has been Implicated In the pathogenesIs of this disease Therefore. when not contral ndlcated, a calcium mtake of 1000-1500 mg/day either by dIet or supplements IS recommended for post- menopausal women Immobilization and prolonged bedrest produce rapid bone loss, while weight-bear- Ing exerCIse has been shown to both reduce bone loss and to Increase bone mass The optimal type and amount of physical activity that might lower the nsk of osteporosls have not been established CONTRAINDICATIONS Estrogens should not be used 10 women or men With any of the following conditions 1 known or suspected cancer of the breast 2 known or suspected estrogen-dependent neoplasia, 3 known or suspected pregnancy (see Boxed Warn 109) 4 undiagnosed abnormal gemtal bleeding 5 active thrombophlebitis or thromboembolic disorders; 6 history of thrombophlebitis, thrombosIs or thromboembolic disorders asso- ciated with previOUS estrogen use WARNINGS 1 InductIOn of Maltgnant Neoplasms Long-term continuous administration of natu- ral and synthetic estrogens In certain animal species Increases the frequency of car- clnomas of the breast. cervIX, vagina, and liver There are now reports that estrogens Increase the nsk of carcmoma of the endometnum In humans (See Boxed Warning) At the present time, there IS no satisfactory eVidence that estrogens gIVen to postmenopausal women Increase the nsk of breast cancer, although a recent long- term follow-up study has raised this POSSibility Because of the am mal data, there IS a need for caution In prescnbmg estrogens for women WIth a strong family history of breast cancer or who have breast nodules flbrocystlc disease or abnormal mammograms 2 Gallbladder DIsease A recent study has reported a two. to threefold rncrease In the nsk of surgically confirmed gallbladder disease In postmenopausal women receIVing oral estrogens similar to the twofold Increase prevlous noted In users of oral contraceptives 3 Effects SImIlar to Those Caused by Estrogen-Progestogen Oral ContraceptIVes There are several senous adverse effects of oral contraceptives and other hlgh-dose oral estrogen treatments most of which have not, up to now, been documented as consequences of postmenopausal estrogen replacement therapy This may reflect the comparatively low doses of estrogen used In postmenopausal women a Thromboemboltc DIsease It IS now well established that users of oral contracep- tiVes have an mcreased nsk of vanous thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocardial infarction Cases of retmal thrombosIs mesentenc thrombosIs. and OptiC neuntls have been reported In oral contraceptive users There IS evidence that the nsk of several of these adverse reactions IS related to the dose of the drug M Increased nsk of postsurgery thromboembolic complications has also been reported In users of oral contraceptIVes If feasible estrogen should be discontinued at least 4 weeks before surgery of the type assoCIated WIth an Increased nsk of thromboembolism, or dunng periods of prolonged Immoblllzahon While an Increased rate of thromboembolic and thrombotic disease In postmenopausal users of estrogens has not been found, this does not rule out the pOSSibility that such an Increase may be present or that subgroups of women who have underlying nsk factors or who are receiving relatively large doses of estrogens may have mcreased nsk Therefore, estrogens should not be used 10 persons WIth active thrombophlebitis or thromboembolic disorders and they should not be used In persons with a history 01 such disorders In assoCIation With estrogen use They should be used with caution In patients with cerebral vascular or coronary artery disease and only for those 10 whom estrogens are clearly needed Large doses of estrogen (5 mg conjugated estrogens per day). comparable to those used to treat cancer of the prostate and breast, have been shown In a large prospective clinical tnalln men to Increase the nsk of nonfatal myocardial mfarctlon, pulmonary embolism, and thrombophlebitis When estrogen doses of this sIZe are used, any of the thromboembolic and thrombotic adverse effects associated with oral contracep- tive use should be considered a clear nsk. b HepatIc Adenoma Benign hepatic adenomas have been associated With the use of oral contraceptives Although bemgn and rare these tumors may rupture and cause death from Intra-2bdomlnal hemorrhage Such lesions have not yet been reported In association with other estrogen or progestogen preparations, but they should be considered IT abdominal pam and tenderness, abdominal mass, or hypovolemic shock occurs In patients recelvmg estrogen Hepatocellular carCInoma has also been re- ported 10 women taking estrogen-contain 109 oral contraceptIVes The causal relation- ship of this malignancy to these drugs IS not known c Elevated Blood Pressure Women uSing oral contraceptIVes sometimes expenence Increased blood pressure WhiCh, 10 most cases, returns to normal upon dlsconhnumg the drug There IS now a report that thIS may occur with use of oral estrogens In the menopause and blood pressure should be mOnitored with estrogen use, especlal If high doses are used Ethlnyl estradiol and conjugated estrogens have been shown to Increase renin substrate In contrast to these oral estrogens transdermallyadmlnls- tered estradiol does not affect remn substrate d Glucose Tolerance A worsening of glucose tolerance has been observed In a slgmflcant percentage of patients on estrogen-containing oral contraceptIVes For this reason, diabetic patients should be careful observed while recelVmg estrogen 4 HypercalcemIa Administration of high doses of estrogens may lead to severe hypercalcemia In patients with breast cancer and bone metastases If hypercalcemia occurs use of the drug should be stopped and appropnate measures should be taken to reduce the serum calcium level PRECAUTIONS General 1 A complete medical and faml history should be taken before initiation of any estrogen therapy The pretreatment and penodlc physical examinations should In- clude speCIal reference to blood pressure breasts. abdomen and pelvIc organs. as well as a cervical Papanicolaou test As a general rule. estrogen should not be prescnbed for longer than 1 year without another physical examinatIOn being performed 2 Because estrogens may cause some degree of fluid retention careful observation IS required when conditions that might be mfluenced by this factor are present (e g., asthma, epilepsy, migraine, and cardiac or renal dysfunction) 3 Certain patients may develop undesirable mamfestatlons of excessIVe estrogemc stimulation such as utenne bleedmg mastodynia, etc 4 Prolonged admmlstratlon of unopposed estrogen therapy has been reported to Increase the nsk of endometnal hyperplasia In some patients Estrogens should be used with caution 10 patients who have or have had endometnosls 5 Studies of the addition of a progestin for 7 or more days of a cycle of estrogen admlmstratlon have reported a lowered incidence of endometnal hyperplasia Mor- phological and biochemical studies of endometnum suggest that 12 to 13 days of progestin are needed to provide maximal maturation of the endometnum and to eliminate any hyperplastic changes Whether this will provide protection from endo- metnal caranoma has not been clearly established There are possible additional nsks that may be associated WIth the inclusion of progestin In estrogen replacement regimens The potential nsks Include adverse effects on carbohydrate and lipid metabolism The choice of progestin and dosage may be Important In mlnlmlzmg these adverse effects 6 Oral contraceptives appear to be assoCIated with an Increased incidence of mental depression Mhough It IS not dear whether this IS due to the estrogenic or progesto- genic component of the contraceptive patients WIth a history of depression should be careful observed 7 Preexisting utenne leiomyomata may Increase In sIZe dunng prolonged estrogen use If this occurs. estrogen therapy should be discontinued while the cause IS investigated 8 In patients with a history of Jaundice dunng pregnancy, there IS an Increased nsk that Jaundice will recur WIth the use of estrogen-contamrng oral contraceptives If Jaundice develops 10 any patient receIVing estrogen the medication should be discon- tinued while the cause IS mvestlgated 9 Estrogens may be poorly metabolized 10 patients with Impaired lIVer function and should be administered with caution 10 such patients 10 Because the prolonged use of estrogens Influences the metabolism of calcium and phosphorus, estrogens should be used with caution In patients with metabolic bone diseases associated WIth hypercalcemia and In patients with renal inSufficiency Infonnation for Patients See Patient Package Insert pnnted below Drug/laboratory Test Interactions The resufis of certain endocnne and liver function tests may be affected by estrogen- containing oral contraceptives The folloWIng changes have been observed with large doses of oral estrogen 1 Increased sulfobromophthalem retention 2 Increased prothrombm time, mcreased factors VII VIII IX and X. decreased antlthrombm 3, Increased noreplnephnne-Induced platelet aggregablhty 3 mcreased thyroxme-bmdlng globulin (TBG). leading to mcreased CIrculating total thyrOId hormone (T 4) as measured by column or radioimmunoassay free T 3 resin uptake IS decreased reflecting the elevated TBG free T 4 concentration IS unal- îered, TBG was not affected In cllmcal tnals of Estraderm 4 reduced response to the metyrapone test. 5 reduced serum folate concentration, 6 Increased serum tnglycende and phospholipid concentration and decreased pregnanediol excretion The pathologist should be Informed that the patient IS receiving estrogen therapy when relevant specimens are submitted Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS and Boxed Warmng Long-term contmuous admmlstratlon of natural and synthetic estrogens In certam ammal species Increases the frequency of carcmomas of the breast, cerviX vagina and liver Pregnancy Category X See CONTRAINDICATIONS and Boxed Warning Estrogens should not be used dunng pregnancy Nursing Mothers As a general pnnClple the administration of any drug to nursing mothers should be done only when clearly necessary Since many drugs are excreted 10 human milk ADVERSE REACTIONS See WARNINGS and Boxed Warning regarding potential adverse effects on the fetus induction of malignant neoplasms. Increased mCldence of gallbladder disease and adverse effects similar to those of oral contraceptives, including thromboembolism The most commonly reported adverse reaction to Est aderm In clinical tnals was redness and Irntatlon at the application site This occurred I n about 17% of the women treated and caused approxlmate 2% to discontinue therapy Reports of rash have been rare The following additional adverse reactions have been reported with estrogemc therapy, Includmg oral contraceptives Gemtounnary System Breakthrough bleeding. spotting change In menstrual flow; Increase In size of utenne fibromyomata, change 10 cervical erosion and amount of cerY1cal secretion Endocnne Breast tenderness, breast enlargement Gastrolntestmal Nausea, vomrtmg, abdominal cramps bloating cholestatic Jaun- dice have ooen observed WIth oral estrogen therapy Eyes Steepenrng of corneal curvature, Intolerance to contact lenses Central Nervous System Headache migraine, dIZZiness MIscellaneous Change In weight edema, change In libido DOSAGE AND ADMINISTRATION The adhesive side of the Estraderm system should be placed on a clean, dry area of the skm on the trunk of the body (mcludlng the buttocks and abdomen) Estraderm should not be applied to the breasts The sites of application must be rotated with an Interval of at least 1 week allowed between applications to a particular Site The area selected should not be oily, damaged or Irntated The waistline should be avoided smce tight clothing may rub the system off The system should be applied Immediately after opening the pouch and removmg the protective liner The system should be pressed firmly In place WIth the palm of the hand for about 10 seconds, makmg sure there IS good contact, especially around the edges In the unlikely event that a system should fall off, the same system may be reapplied If necessary. a new system may be applied In either case the onglnal treatment schedule should be continued Initiation of Therapy Treatment of menopausal symptoms IS usualy inrtlated WIth Estraderm 005 mg applied to the skin twice weekly The dosage should be adjusted as necessary to control symptoms The lowest dosage necessary forthe control of symptoms should be used, especially In women with an Intact uterus Attempts to taper or discontinue the medication should be made at 3- to 6-month Intervals Prophylactic therapy with Estraderm to prevent postmenopausal bone loss should be initiated with the 0 05 mgJday dosage as soon as possible after menopause The dosage may 00 adjusted If neæssary to control concurrent menopausal symptoms Dlscontmuatlon of estrogen replacement therapy may reestablish the natural rate of bone loss In women not current taking oral estrogens treatment with Estraderm may be Initiated at once In women who are currently taking oral estrogen treatment WIth Estraderm should be Initiated 1 week after withdrawal of oral hormone replacement therapy, or sooner If menopausal symptoms reappear In less than 1 week Therapeutic Regimen Estraderm therapy may be gIVen continuously In patients who do not have an mtact uterus In those patients with an mtact uterus Estraderm may be given on a cyclic schedule (e g 3 weeks on drug followed by 1 week off drug) HOW SUPPLIED Estradenn 005 (estradiol transdermal system)-each 10 cm 2 system contains 4 mg of estradiol USP for nominal" delivery of 0 05 mg of estradiol per day Patient Calendar Pack of 8 Systems .... . NDC 0083-2310-08 Carton of 6 Pahent Calendar Packs of 8 Systems NDC 0083-2310-62 Carton of 1 Patient Calendar Pack of 24 Systems NDC 0083-2310-24 Estradenn 0.1 (estradiol transdermal system) - each 20 cm 2 system contains 8 mg of estradiol USP for nominal delivery of 0 1 mg of estradiol per day Patient Calendar Pack of 8 Systems NDC 0083-2320-08 Carton of 6 Patient Calendar Packs of 8 Systems NDC 0083-2320-62 Carton of 1 Patient Calendar Pack of 24 Systems NDC 0083-2320-24 .See DESCRIPTION Do not store above 86"F (3crG) Do not store unpouched App Immedlate upon removal from the protective pouch C91-37 (Rev 9/91) C I B A CIBA Pharmaceutical Company Division of CIBA-GEIGY Corporation Summit, New Jersey 07901 @ 1992 CIBA-GEIGY Corporation